The poor prognosis of patients with advanced lung cancer, with a median survival of less than 12 months, indicates an obvious need for more effective treatments. Although fluoropyrimidines are not commonly used to treat NSCLC, these agents have demonstrated improvements in survival in the adjuvant setting. The recently introduced oral fluoropyrimidine capecitabine is interesting for evaluation in NSCLC, given its synergistic potential in combination with paclitaxel or docetaxel, drugs that are among the most active in the treatment of NSCLC. This synergy is believed due to upregulation of the enzyme thymidine phosphorylase (TP), which is responsible for the preferential tumor activation of capecitabine. We have developed a novel schedule for the combination of docetaxel and capecitabine that takes into consideration the time dependency of TP upregulation by docetaxel. This schedule is aimed to provide for repetitive stimulation of TP, and for capecitabine administration at the predicted times of maximal TP upregulation. Using this schedule, we demonstrated activity in NSCLC previously treated with chemotherapy. Evaluation of TP, dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) expression m tumor blocks from a group of these patients suggested that TP tumor to normal and TP/DPD ratios, as well as tumor nuclear TS, may be useful as predictors of response to treatment. We propose to study this combination/schedule in NSCLC patients not previously treated with chemotherapy. Tumor and normal lung tissue will be evaluated for potential predictors of response to this combination. In addition, DPD activity in peripheral mononuclear cells will be measured to establish relationships to toxicity within the DPD normal distribution. The proposed research has the potential of identifying a new combination treatment for advanced NSCLC and providing a predictive approach to identify patients more amenable to treatment response to the combination. Confirmation of our working hypothesis may lead to a new treatment paradigm suitable for evaluation in the adjuvant setting.